When mice mislead, medical research lands in the trap

An article in today's New York Times highlights just-published work by Massachusetts General Hospital researchers and Stanford genomics expert Ron Davis, PhD, in which the scientists presented "stunning evidence that the mouse model has been totally misleading for at least three major killers - sepsis, burns and trauma." As a result, according to the Times article, "years and billions of dollars have been wasted following false leads."

The newspaper story is referring to a Proceedings of the National Academy of Sciences study that writer Gina Kolata says may help explain why every one of nearly 150 drugs tested at huge expense in patients with sepsis has failed.

This work goes back several years, with Davis and his associates finding patterns of gene activity that seemed to predict which sepsis victims will live and which will die. The researchers tried to publish their results in several journals but were initially rebuffed because they hadn't tested their findings in mice to see if the same things happened, according to the article:

“They were so used to doing mouse studies that they thought that was how you validate things,” [Davis] said. “They are so ingrained in trying to cure mice that they forget we are trying to cure humans."

"That started us thinking,” he continued. “Is it the same in the mouse or not?” The group decided to look, expecting to find some similarities...

But when the investigators looked, there were none at all. In fact, some genes that were "turned on" by sepsis in mice were "turned off" in humans. Further, in humans, similar genes were activated by sepsis, trauma and burns - three conditions in which the immune system overreacts and inflicts more damage to the body than the bacteria, knock to the head or house fire, respectively, that originally caused the problem. But in mice, these three different types of stimuli trigger three quite different gene-activation patterns.

So, a drug that might work in a human could have the opposite effect in a mouse. And vice versa.

The man/mouse mismatch, intriguingly, shows up in other places, too. For instance, a recent study led by Stanford immunologist Mark Davis, PhD, suggests that experimental mice - who spend their entire lives in artificial, ultra-germ-free environments - may be a poor model for adult humans' more battle-hardened immune systems, which have acquired quite a bit of savoir faire.

And in another study a few months back, Stanford drug-development expert Gary Peltz, MD, PhD, developed mice with humanized livers, explicitly to address another disparity that can easily result in costly failures of new drugs in clinical trials: Mice's livers, being different from ours, often metabolize new experimental drugs quite differently from the way ours would.